Clinical Science (2012) 122, 591–597 (Printed in Great Britain) doi:10.1042/CS20110520
Glutamine and glutathione at ICU admission in
relation to outcome
Paul Castillo RODAS, Olav ROOYACKERS, Christina HEBERT, Åke NORBERG and
Jan WERNERMAN
Department of Anesthesiology and Intensive Care Medicine at Karolinska University Hospital Huddinge, Stockholm, Sweden
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Glutamine depletion is demonstrated to be an independent predictor of hospital mortality in
ICU (intensive care unit) patients. Today glutamine supplementation is recommended to ICU
patients on parenteral nutrition. In addition to glutamine, glutathione may be a limiting factor
in ICU patients with MOF (multiple organ failure). To study the prevalence of glutamine and
glutathione depletion an observational study was performed. The results were analysed in relation
to mortality and the conventional predictors of mortality outcome, APACHE II (Acute Physiology
and Chronic Health Evaluation II) and SOFA (Sequential Organ Failure Assessment). Consecutive
patients admitted to the ICU at Karolinska University Hospital Huddinge were studied. Patient
admission scoring of APACHE II and SOFA were registered as well as mortality up to 6 months.
Plasma glutamine concentration and whole blood glutathione status at admittance were analysed.
The admission plasma glutamine concentrations were totally independent of the conventional risk
scoring at admittance, and a subnormal concentration was an independent predictor of mortality.
In addition, glutathione redox status was also an independent mortality predictor, but here a
normal ratio was the risk factor. In both cases the mortality risk was mainly confined to the
post-ICU period. A low plasma concentration of glutamine at ICU admission is an independent
risk factor for post-ICU mortality. The possible benefit of extending glutamine supplementation
post-ICU should be evaluated prospectively.
INTRODUCTION
Glutamine depletion is demonstrated to be an independent predictor of mortality in a group of ICU (intensive
care unit) patients when dichotomized with a cut-off at a
plasma glutamine concentration of 420 μmol/l [1].
This finding is a major rational for the institution
of extra glutamine supplementation to ICU patients. In
single-centre studies of ICU patient needing parenteral
nutrition, intravenous glutamine supplementation has
been shown to reduce mortality [2,3]. It has been
suggested that the plasma glutamine concentration may
be an indicator of an insufficient availability of glutamine
[4], although the endogenous production of glutamine in
sepsis and MOF (multiple organ failure) is demonstrated
to be maintained [5,6]. Further knowledge of glutamine
kinetics and the epidemiology of glutamine depletion are
needed in order to correctly estimate the possible need for
exogenous glutamine supplementation, the appropriate
selection of patients and the design of studies addressing
the effects of such supplementation.
It is also known that plasma glutamine concentration
is fairly stable in ICU patients with MOF staying for an
extended period of time in the unit regardless of being fed
with conventional enteral or parenteral formulations not
supplemented with glutamine [7,8]. On the other hand,
when intravenous glutamine supplementation of 0.3 g of
glutamine/kg of body weight per day is given as a constant
infusion (separate or as a part of an amino acid mixture),
plasma glutamine concentration is normalized [7,9,10].
Key words: critically ill, glutamine, glutathione, intensive care unit, mortality, redox status.
Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II; ICU, intensive care unit; MOF, multiple organ
failure; ROC, receiver operating characteristic; SOFA, Sequential Organ Failure Assessment.
Correspondence: Professor Jan Wernerman (email [email protected]).
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In addition to glutamine, glutathione may be a limiting
factor in ICU patients with MOF. The possible predictive
value of glutathione status has not been investigated
in ICU patients. Furthermore to correctly estimate
glutathione status a measure of the glutathione redox
status in addition to the overall concentration is needed.
For glutamine, plasma concentrations give a fair
estimate of availability and status. For glutathione on the
other hand, plasma concentration is low and glutathione
redox status is difficult to measure reliably in the plasma
fraction, although concentration is higher in ICU patients
as compared with controls or elective surgery patients
[11–14]. In addition redox status in plasma may not
be representative for the intracellular status. Therefore
whole blood determinations give the best idea about
glutathione status. In an observational study, it was
demonstrated that MOF patients in the ICU were low
in total glutathione, approximately 60–70 % of the level
seen in healthy volunteers or in stable out-patients with
COPD (chronic obstructive pulmonary disease) [13],
similar results are reported in paediatric ICU patients
[15]. In addition, the GSH/total glutathione ratio (a
reflection of glutathione redox status) was reduced.
In parallel with glutamine status, the glutathione status in
whole blood was demonstrated to be stable over time
in the ICU.
To address these questions, we performed a pragmatic
but well-controlled observational study in patients
consecutively admitted to the ICU. Plasma glutamine
concentration and whole blood glutathione status were
determined within 48 h after ICU admission. The results
were analysed in relation to mortality and the conventional predictors of mortality outcome, APACHE II
(Acute Physiology and Chronic Health Evaluation II)
and SOFA (Sequential Organ Failure Assessment).
MATERIALS AND METHODS
Consecutive patients admitted to the ICU at Karolinska
University Hospital Huddinge during the period
September 2006–March 2007 were included in the
study. The unit is a mixed ICU, but without thoracic,
neurosurgery and trauma cases. There are also some
paediatric patients admitted to the unit. The study
protocol was approved by the Regional Ethical Review
Board in Stockholm and patients or their next of kin
were informed orally and in writing before obtaining their
informed consent.
Inclusion criteria for the study were admittance to
the ICU during the study period plus informed consent
and sampling within 24 h after admittance. Exclusion
criteria were the absence of informed consent at 48 h
after admittance, paediatric patients under the age of 18,
glutamine supplementation before ICU admittance or
failure of sampling within 24 h of admittance.
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From the log at the unit a drop-out analysis was also
performed including some basic characteristics of the
non-included patients during the study period.
At the time of the study the routine in the unit was early
full feeding, usually starting within 48 h, a combination of
enteral and parenteral nutrition. The parenteral nutrition
given did not contain any glutamine and no separate
glutamine supplementation was given during this time
period. The enteral nutrition contained glutamine, but
was not enriched with glutamine
Blood samples for glutamine analysis were taken in
heparinized tubes and centrifuged within 30 min and the
plasma was stored at − 80 ◦ C pending analysis using
HPLC after pre-column derivatization and with an
internal standard of norvalin [8].
Blood samples for glutathione analysis were immediately precipitated with 14 % HClO4 , containing 2 mmol
phenanthroline. After mixing the samples were frozen in
liquid nitrogen, and thereafter stored at − 80 ◦ C pending
analysis, which was done in 2009 (after 18 months of
storage). Just before analysis the samples were centrifuged
at 12 500 g for 15 min at 4 ◦ C. Both GSH and total [after
reduction with DTT (dithiothreitol)] glutathione were
then analysed in whole blood using HPLC as described
previously in detail [13,16].
All results are given as means +
− S.D., unless otherwise
indicated. Student’s t test, ANOVA and Pearson’s linear
regression analysis were used when applicable. For
mortality data, Fisher’s exact two-tailed test was used.
Univariate logistic regression and stepwise multiple
logistic regression on predictors of mortality were
performed using the software NCSS 2007.
RESULTS
The target was to include 200 patients. During the study
period there were 291 admissions of patients >17 years
of age. From these, 174 patients were included and 117
patients were not included (Figure 1). The characteristics
of these two groups are given in Table 1. A difference
in the length of ICU stay was observed. Mortality data
were checked in the Swedish national registry, where all
patients are identified by their unique personal number.
There were no missing mortality data.
When patients were dichotomized with a cut-off
at plasma glutamine concentration of 420 μmol/l, the
groups were comparable in characteristics (Table 1), but
a difference in 6-month all-cause mortality was observed,
33 out of 76 patients compared with 27 out of 98 patients
(P = 0.037) for <420 and >420 μmol/l respectively. When
patients were divided into quartiles and mortality was
specified in ICU mortality and post-ICU all-cause 6month mortality (Figure 2), it became obvious that the
dichotomization at a glutamine plasma concentration
of 420 μmol/l came very close to the median value
Glutamine at ICU admission
Figure 1 A CONSORT diagram illustrating the screening of
all admitted patient during the study period
Non-included patients were divided into <24 h of ICU stay, with a mortality of
34 % and>24 h of ICU stay with a mortality of 52 %. The latter group had an
ICU stay of 4 (3, 7) days (values is the median and interquartile range).
430 μmol/l. Furthermore, the 50 % of patients with the
lower admission plasma glutamine concentration had a
higher mortality, the major part of which was postICU all-cause 6-month mortality. The admission plasma
glutamine concentrations were totally independent of the
risk scoring in terms of APACHE II scores (Figure 3) or
SOFA scores (results not shown).
Whole blood total glutathione concentration was
514 +
− 136 μmol/l, whereas the GSH fraction was
280 +
− 105 μmol/l, resulting in a GSH/total glutathione
ratio in whole blood, a reflection of glutathione redox
status, of 0.55 +
− 0.14. For the total concentration of
glutathione and the concentration of GSH in whole
blood, as well as the GSH/total glutathione ratio in
whole blood, there was no relationship with predicted
mortality in terms of APACHE II scores (Figure 4) and
SOFA scores (results not shown). In addition, when the
Figure 2 All-cause 6-month mortality (open bars) and ICU
mortality (filled bars) of consecutive patients admitted
to the general ICU (n = 174) at Karolinska Huddinge
divided into quartiles according to the admittance plasma
glutamine concentration
Mortality is different in between the quartiles, where the two lower quartiles are
different from the two higher (P = 0.037).
patients were divided into quartiles according to the total
concentration of glutathione and the concentration of
GSH in whole blood, no relationship to the predicted
or actual mortality was observed (results not shown).
In contrast, when patients were divided into quartiles
according to the GSH/total glutathione ratio in whole
blood (Figure 5), 6-month all-cause mortality was higher
for the quartile with the highest ratio (21 out of 43
patients) as compared with in the lower three quartiles
(37 out of 126 patients) (P = 0.026). The empirical
ROC (receiver operating characteristic) curve of the
GSH/total glutathione ratio compared with mortality
[AUC (area under the curve) 0.56, P = 0.18] confirmed
the suggested cut-off for the GSH/total glutathione ratio
of 0.66; characteristics of the patients according to this
dichotomization is given in Table 1.
Table 1 Characteristics of the patients
Characteristics of all of the patients admitted to the ICU during the inclusion period are given in the left-hand part of the Table, characteristics of the included
patients dichotomized at a plasma glutamine (Gln) concentration of 420 μmol/l are given in the middle part of the Table, and those dichotomized at a GSH/total
glutathione ratio (Redox) of 0.66 in whole blood are given in the right-hand part of the Table. Results are presented as means +
− S.D. or median (inter-quartile
range) as appropriate. Statistical analysis by Student’s t test∗ , Mann–Whitney U test† or Fisher’s exact two-tailed test‡. LOS, length of study.
Characteristic
Included
(n = 174)
Not included
(n = 117)
P
Gln<420
(n = 76)
Gln>420
(n = 98)
P
Redox 0.65
(n = 126)
Redox >0.66
(n = 43)
P
Age (years)
APACHE II
SOFA
LOS (days)
Gender (male %)
6-Month mortality (%)
59 +
− 18
19 +
−7
7+
−4
2 (1, 5)
59
34.5
54 +
− 18
19 +
−9
6+
−5
1 (1, 2)
51
38.5
0.02∗
1.00∗
0.19∗
<0.001†
0.23‡
0.53‡
63 +
− 16
20 +
−7
7+
−4
2 (1, 6)
59
43
57 +
− 18
19 +
−8
7+
−4
2 (1, 4)
58
28
0.03∗
0.27∗
0.34∗
0.96†
1.00‡
0.04‡
59 +
− 18
19 +
−8
7+
−4
1 (1, 4)
60
17
61 +
− 18
20 +
−8
8+
−4
4 (1, 8)
58
49
0.62∗
0.68∗
0.007∗
0.007†
1.00‡
0.03‡
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Figure 3 Relationship between the plasma concentration of
glutamine of consecutive patients admitted to the general
ICU (n = 174) at Karolinska Huddinge and their APACHE II
scores
No correlation was seen (P = 0.46)
Figure 5 All-cause 6-month mortality (open bars) and ICU
mortality (filled bars) of consecutive patients admitted to
the general ICU (n = 169) at Karolinska Huddinge divided
into quartiles according to the GSH/total glutathione (tGSH)
ratio of whole blood at admittance reflecting glutathione
redox status
Mortality is different in between the quartiles, where the highest quartile is
different from the three lower (P = 0.026).
admission glutamine plasma concentration of <400 or
>930 μmol/l and a whole blood GSH/total glutathione
ratio 0.66 could also be identified as independent
predictors of mortality. In total, 82 % of the total 6-month
all-cause mortality was explained by these factors.
DISCUSSION
Figure 4
ratio in
admitted
Huddinge
Relationship between the GSH/total glutathione
whole blood reduced of consecutive patients
to the general ICU (n = 169) at Karolinska
compared with their APACHE II scores
No correlation was seen (P = 0.93).
Out of the data presented, a stepwise logistic
regression analysis was performed (Table 2). In an
explorative analysis, the empirical ROC curve of
plasma glutamine concentration compared with 6-month
mortality crossed the line of identity at a plasma
glutamine concentration of 675 μmol/l, suggesting a Ushaped influence of plasma glutamine concentration on
mortality. ROC curves at data below (n = 154) and over
(n = 20) 675 μmol/l demonstrated cut-offs (maximum of
sensitivity + specificity) at 403 and 928 μmol/l respectively. These values were rounded to 400 and 930 μmol/l
respectively, in the further exploration of predictors of
death within 6 months. As expected APACHE II served
as the major mortality predictor, but in addition age, an
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Our results reproduced the findings of Oudemans-van
Straaten et al. [1] of admission plasma glutamine as an
independent predictive factor for mortality also in an
unselected patient data from a mixed general ICU. In that
study, the endpoint was hospital mortality. An additional
finding in the present study was that the mortality
difference was confined to the post-ICU period of the
all-cause 6-month mortality.
Related to differences in the organization of health care
in different countries, ICU mortality and hospital mortality may not be immediately comparable. The Swedish
health care insurance system allows for a 6-month allcause mortality analysis with a minimal loss to follow-up.
It may be a Swedish situation that the post-ICU mortality
exceeds the ICU mortality, but the obvious relevance of
this type of follow-up must be emphasized.
The increase in correctly predicted outcome from 70
to 75 % by adding a pathological low or high glutamine
concentration at admittance may not seem dramatic, but
the difference may be illustrated graphically (Figure 6).
This points out that this difference in terms of mortality
risk for an individual patient may be dramatically
different.
Glutamine at ICU admission
Table 2 Prediction of 6-month mortality in ICU patients
Univariate analysis (n = 174) and stepwise multiple logistic regression analysis (n = 169) are shown. Gln, plasma glutamine concentration (μmol/l);
rGSH/tGSH, GSH/total glutathione ratio in whole blood; OR, odds ratio; CI, confidence interval.
(a) Univariate analysis
Gln<420
Gln<400
Gln>930
Gln<400 or >930
rGSH/tGSH>0.65
Gender (male)
APACHE (per point)
Age (per year)
OR (CI)
P
2.02
2.41
4.11
3.22
2.17
1.35
1.14
1.06
0.029
0.007
0.043
<0.001
0.032
0.36
<0.001
<0.001
(1.07–3.80)
(1.26–4.59)
(0.99 – 17.1)
(1.68–6.16)
(1.07–4.40)
(0.71–2.57)
(1.09–1.21)
(1.03–1.08)
(b) Stepwise multiple logistic regression analysis
Intercept
APACHE (per patient)
Gln <400 or >930
Age (per year)
rGSH/tGSH >0.65
β
OR (CI)
P
Correct (%)
− 6.43
0.13
1.08
0.04
0.85
0.002 (0.0002–0.016)
1.14 (1.07–1.22)
2.95 (1.38–6.32)
1.04 (1.01–1.07)
2.35 (1.02–5.41)
<0.001
0.005
0.006
<0.001
70.1
74.6
78.1
81.7
Figure 6 Simulation of the additional prediction of
mortality rate from an out of range glutamine concentration
at admittance
Black line is the APACHE-predicted mortality rate if the plasma glutamine
concentration at admittance is within the range 400–930 μmol/l. With an
admittance glutamine concentration outside of that range, the dotted curve
represents the predicted mortality rate, suggesting a mortality rate of 50 % at
APACHE 20 in contrast with APACHE 29.5 if the glutamine concentration is not
considered.
When performing the stepwise multiple regression
analysis it became obvious that the admission plasma
glutamine concentration compared with mortality curve
had a U-shape, with an increased mortality also for
very high-plasma glutamine concentrations. It has been
reported previously that patients with acute fulminant
liver failure (but not acute-on-chronic liver failure) may
have such high concentrations [17]. Most of the small
number of patients with very high plasma glutamine
concentrations in this study had acute liver failure.
Glutamine kinetics in this subgroup of patients is poorly
understood and need to be studied further [18].
The recently presented results from the Scandinavian
glutamine study suggest that intravenous glutamine
supplementation may reduce ICU mortality, but that the
mortality advantage is not maintained post-ICU [19]. It
was hypothesized that this may be related to the discontinuation of glutamine supplementation at ICU discharge. The present observational study is also suggestive
that glutamine depletion may be related to post-ICU
mortality (Figure 7). The need for prospective studies
extending glutamine supplementation beyond ICU stay
in glutamine depleted patients is therefore obvious.
In addition our results confirm the data from earlier
pilot studies in ICU patients with MOF that total glutathione and GSH concentrations in whole blood are low
in ICU patients. The levels of these concentrations were
not found to be related to ICU mortality outcome. Not
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Figure 7 Individual plasma glutamine concentrations at ICU
admission compared with outcome
Note the log-scale of the y -axis. Grey area represents normal values 400–930 μM.
Median in each group is depicted as a line.
surprisingly the redox status of glutathione was demonstrated to be related to mortality outcome, but it was quite
unexpected that the quartile with the highest ratio of GSH
and total glutathione carried the highest mortality.
A possible explanation for an increased mortality risk
associated with a redox ratio of glutathione closer to
the normal range is that the scavenging properties of
glutathione has been less utilized among these individuals.
The interpretation of this quite original finding should
consider a number of factors: the sampling and analysis
of whole blood as an indicator of glutathione status,
sampling during the initial 48 h of ICU stay, the timecourse of ICU stay and the ICU mortality compared
with the post-ICU mortality (Figure 4).
We know from earlier studies in selected groups of
patients that the plasma concentration of glutamine, as
well as the whole blood redox status of glutathione,
do not change over time during an ICU stay when no
specific supplementation is given [13]. Therefore should
the admission values presented here be representative
of the status of the particular patient during ICU stay?
We know that the plasma glutamine concentration may
be influenced by exogenous glutamine supplementation
[7,9,10,20], but so far no treatment to influence the
redox status of glutathione in whole blood in this patient
group has been presented. Beside exogenous glutamine
supplementation, selenium supplementation may have an
effect, as the activity of glutathione peroxidase responds
to selenium supplementation [21]. Controlled studies
addressing these hypotheses are needed.
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In the characteristics of the patient groups with a
higher mortality risk according to the glutamine and
glutathione status some differences were seen. It must
be underlined that these rather speculative observations
are merely hypothesis generating. Nevertheless, patients
with a low plasma glutamine concentration tend to have
high post-ICU mortality, wheras patients with a high
redox ratio of glutathione in whole blood have a longer
ICU length of stay and again a higher post-ICU mortality
(Table 1). None of these groups stand out in terms of
admittance APACHE II scores, but the risk group in
terms of the high glutathione redox ratio were higher
in initial 24 h SOFA score.
Observational studies always have the limitation that
they basically only represent the group of patients
actually studied. In the present report, we provide
information of not only the studied patients, but also
the patients not included in the study, in order to provide
complete information. As expected, the majority of the
drop-outs were short stayers (primarily during weekends). This is reflected in that the median ICU length of
stay for this group was 1 day (Figure 1). In addition, there
were also a limited number of patients, where informed
consent and sampling failed within the stipulated time
limit of 48 h, or where withholding of treatment was
decided before an informed consent was obtained.
A remarkable finding in the missing data analysis was
the high APACHE II score and the high mortality in the
group of mainly short stayers not included in the study.
To some extent, this is probably a reflection of the rather
extreme shortage of ICU beds at the time of the study.
The important issue is of course to what degree our data
can be generalized. Are our situations and our case-mix
too special? We think that the ICU situation reflected
in the patient data, with a comparatively short length of
ICU stay combined with a low ICU mortality but high
post-ICU mortality is special. Nevertheless, the overall
outcome of our patients is probably not different from
what is seen in places with a different organization of the
ICU compared with the rest of the hospital.
In conclusion, low plasma concentration of glutamine
at ICU admission is an independent risk factor for postICU mortality.
AUTHOR CONTRIBUTION
Olav Rooyackers and Jan Wernerman conceived the
study. Paul Rodas, Olav Rooyackers, Christina Hebert
and Jan Wernerman designed the study protocol. Paul
Rodas and Jan Wernermans performed the clinical part of
study. Christina Hebert and Olav Rooyackers analysed
the samples. Paul Rodas, Olav Rooyackers Christina
Hebert, Åke Norberg and Jan Wernerman performed the
calculations and statistics. Paul Rodas and Jan Wernerman
wrote the paper. Paul Rodas, Olav Rooyackers, Christina
Glutamine at ICU admission
Hebert, Åke Norberg and Jan Wernerman revised the
paper.
ACKNOWLEDGEMENTS
We are indebted to the excellent nursing skills of Ms
Gunilla Herman and Ms Viveka Gustafsson, and the
excellent analytical skills of Ms Eva Skoog Nejman. The
analyses were performed at the Clinical Research Centre
(KFC) at Karolinska Huddinge.
FUNDING
This study was supported by the Swedish Research
Council [grant numbers 2006-5528, 142144], and through
the Regional Agreement on Medical Training and Clinical
Research (ALF) [grant numbers 583529, 501033] between
Stockholm County Council and Karolinska Institute.
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Received 7 October 2011/21 December 2011; accepted 17 January 2012
Published as Immediate Publication 17 January 2012, doi:10.1042/CS20110520
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